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Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets for Moderate to Severe Chronic Low Back Pain

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01789970
Recruitment Status : Completed
First Posted : February 12, 2013
Results First Posted : April 5, 2017
Last Update Posted : June 5, 2017
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Low Back Pain
Interventions Drug: Hydrocodone ER
Drug: Placebo
Enrollment 625
Recruitment Details A total of 845 patients with moderate to severe chronic low back pain were screened at 78 centers in the U.S.
Pre-assignment Details Of the 625 patients enrolled, 2 patients withdrew consent before taking any study drug. Of 623 patients who were enrolled and received study drug, 371 patients achieved a successful dose of hydrocodone extended-release (ER) tablets and were randomly assigned to receive hydrocodone ER or placebo during the double-blind treatment period
Arm/Group Title Hydrocodone ER (Open-Label Titration Period) Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain. Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo. Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Period Title: Open-label Titration Period
Started 625 0 0
Safety Analysis Set 623 [1] 0 0
Completed 371 0 0
Not Completed 254 0 0
Reason Not Completed
Adverse Event             68             0             0
Lack of Efficacy             31             0             0
Withdrawal by Subject             31             0             0
Protocol Violation             18             0             0
Lost to Follow-up             5             0             0
Noncompliance to study drug admin             11             0             0
Noncompliance with study rescue meds             2             0             0
Noncompliance with study procedures             8             0             0
Pregnancy             2             0             0
Not specified             76             0             0
Dropped out prior to dosing             2             0             0
[1]
Two enrolled patients were not treated
Period Title: Double-blind Treatment Period (12 Weeks)
Started 0 180 191
Full Analysis Set and Safety Set 0 179 [1] 191
Completed 0 130 147
Not Completed 0 50 44
Reason Not Completed
Adverse Event             0             9             15
Lack of Efficacy             0             17             5
Withdrawal by Subject             0             7             9
Protocol Violation             0             9             7
Noncompliance to study drug admin             0             2             2
Noncompliance with study procedures             0             2             1
Lost to Follow-up             0             1             2
Pregnancy             0             1             0
Not specified             0             1             3
Dropped out prior to dosing             0             1             0
[1]
One participant was randomized but not treated.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period) Total
Hide Arm/Group Description Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo. Participants were administered extended-release hydrocodone tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period. Total of all reporting groups
Overall Number of Baseline Participants 180 191 371
Hide Baseline Analysis Population Description
Intent to treat population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 180 participants 191 participants 371 participants
51.8  (12.51) 51.7  (13.48) 51.8  (13.00)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 180 participants 191 participants 371 participants
<= 65 years
154
  85.6%
156
  81.7%
310
  83.6%
> 65 years
26
  14.4%
35
  18.3%
61
  16.4%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 180 participants 191 participants 371 participants
Female
92
  51.1%
97
  50.8%
189
  50.9%
Male
88
  48.9%
94
  49.2%
182
  49.1%
Race  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 180 participants 191 participants 371 participants
White
129
  71.7%
133
  69.6%
262
  70.6%
Black
41
  22.8%
39
  20.4%
80
  21.6%
Asian
8
   4.4%
13
   6.8%
21
   5.7%
American Indian or Alaska Native
2
   1.1%
2
   1.0%
4
   1.1%
Native Hawaiian or other Pacific Islander
0
   0.0%
1
   0.5%
1
   0.3%
Other
0
   0.0%
3
   1.6%
3
   0.8%
Ethnicity  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 180 participants 191 participants 371 participants
Hispanic or Latino
23
  12.8%
24
  12.6%
47
  12.7%
Non-Hispanic and non-Latino
156
  86.7%
167
  87.4%
323
  87.1%
Unknown
1
   0.6%
0
   0.0%
1
   0.3%
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 180 participants 191 participants 371 participants
31.5  (8.22) 31.3  (7.37) 31.4  (7.78)
Participant Opioid Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 180 participants 191 participants 371 participants
Opioid-naive
105
  58.3%
110
  57.6%
215
  58.0%
Opioid-experienced
75
  41.7%
81
  42.4%
156
  42.0%
[1]
Measure Description: Opioid-naïve patients were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening. Opioid-experienced patients were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening. Opioid-experienced patients requiring more than 135 mg/day of oxycodone, or equivalent, during the 14 days before study entry were excluded from the study.
Duration Since Diagnosis of Chronic Low Back Pain  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 180 participants 191 participants 371 participants
11.5  (10.35) 11.3  (10.29) 11.4  (10.31)
Duration of Opioid Therapy  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 180 participants 191 participants 371 participants
2.9  (3.76) 3.5  (4.85) 3.2  (4.37)
Average Daily Hydrocodone Equivalent Dose  
Mean (Standard Deviation)
Unit of measure:  Mg
Number Analyzed 180 participants 191 participants 371 participants
18.2  (28.55) 22.1  (30.18) 20.2  (29.43)
1.Primary Outcome
Title Change From Baseline to Week 12 of the Treatment Period in Weekly Average of Daily Worst Pain Intensity (WPI)
Hide Description

The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their worst pain intensity over the last 24 hours. Weekly WPI scores averaged daily scores collected over the previous 7 days for each analysis visit. Negative change from baseline scores indicate improvement in pain control.

The analysis included WPI data observed before discontinuation of study drug and was based on the multiple imputations (MI) method to handle missing scores at week 12. Consistent with the recommendations of the National Academy of Sciences (NAS) report (Panel on Handling Missing Data in Clinical Trials 2010), the MI method includes an assumption of missing at random (MAR) and takes into account a potential bias toward the active-drug treatment group for patients who discontinued study drug because of adverse events.

Time Frame Days -6 to 0 of Treatment Period (baseline), Week 12 of Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 179 191
Mean (Standard Error)
Unit of Measure: units on a scale
0.71  (0.145) 0.07  (0.134)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period)
Comments The least squares means of the change from baseline to week 12 in WPI were compared between the active drug and placebo treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments 5% significance level
Method ANCOVA
Comments The model included treatment, study center, opioid status, and baseline WPI score.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.26 to 1.00
Estimation Comments Placebo - Hydrocodone ER
2.Secondary Outcome
Title Change From Baseline to Week 12 of the Treatment Period in Weekly Average Pain Intensity (API)
Hide Description

The API over the last 24 hours was recorded daily by patients in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described the average pain intensity over the last 24 hours. Weekly API scores averaged daily scores collected over the previous 7 days for each analysis visit. Negative change from baseline scores indicate improvement in pain control.

The analysis included API data observed before discontinuation of study drug and was based on the MI method to handle missing scores at week 12. Consistent with the recommendations of the National Academy of Sciences (NAS) report (Panel on Handling Missing Data in Clinical Trials 2010), the MI method includes an assumption of missing at random (MAR) and takes into account a potential bias toward the active-drug treatment group for patients who discontinued study drug because of adverse events.

Time Frame Days -6 to 0 of Treatment Period (baseline), Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 179 191
Mean (Standard Error)
Unit of Measure: units on a scale
0.57  (0.126) 0.02  (0.116)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period)
Comments The least squares means of the change from baseline to week 12 in API were compared between the active drug and placebo treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments 5% significance level
Method ANCOVA
Comments The model included treatment, study center, opioid status, and baseline WPI score.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.25 to 0.91
Estimation Comments Placebo - Hydrocodone ER
3.Secondary Outcome
Title Kaplan-Meier Estimates for Time to Loss of Efficacy
Hide Description Time to loss of efficacy was defined as discontinuation of study drug for lack of efficacy or the start of excessive rescue medication while taking study drug. Excessive rescue medication usage was defined as 10 or more days of rescue medication usage in any 14 consecutive days at a total of 15 mg (hydrocodone-equivalent) or higher each day during the post 2-week tapering period of the double-blind treatment period.
Time Frame Day 1 to Week 12 of Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
The full analysis set, which includes all randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline efficacy observation.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 179 191
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Insufficient number of participants with loss of efficacy
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.059
Comments 5% significance level
Method Wald chi-square
Comments Cox proportional hazards model with treatment, baseline worst pain intensity (WPI), opioid status, and center in the model
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
0.5 to 1.01
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants With a 30% or Greater Increase in Weekly Average Pain Intensity (API) From Baseline to Week 12 Visit, and an Average API Score of 5 or Higher at Week 12
Hide Description The API over the last 24 hours was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described the average pain intensity over the last 24 hours. Weekly API scores averaged daily scores collected over the previous 7 days for each analysis visit.
Time Frame Days -6 to 0 of Treatment Period (baseline), Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, including participants with observed weekly average API for week 12
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 133 152
Measure Type: Number
Unit of Measure: percentage of participants
API increase >=30% and API >=5 18.8 12.5
API increase >=30% 36.1 21.1
API >=5 24.1 16.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period)
Comments API increase >=30% and API >=5
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0293
Comments 5% significance level
Method Regression, Logistic
Comments stratified by center with the following effects: treatment group, baseline API, and opioid status.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.67
Confidence Interval (2-Sided) 95%
0.47 to 0.96
Estimation Comments Hydrocodone ER / Placebo
5.Secondary Outcome
Title Change From Baseline to Final On-Treatment Visit in Roland Morris Disability Questionnaire (RMDQ) Score
Hide Description The RMDQ is a patient-rated, 24-question evaluation used to assess acute disability associated with low back pain. Each question is answered with a YES or NO response, and each YES response is given 1 point. Scores on the RMDQ range from 0 to 24, with higher scores indicating greater disability. Negative change from baseline scores indicate improvement in level of disability.
Time Frame Days 7-14 of Titration Period (baseline), Week 12 or end of study visit during the Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set, including participants with RMDQ score for the final on-treatment visit.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 171 178
Mean (Standard Deviation)
Unit of Measure: units on a scale
-1.9  (4.47) -1.5  (4.70)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo (Double-blind Treatment Period), Hydrocodone ER (Double-blind Treatment Period)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.557
Comments 5% significance level
Method ANCOVA
Comments Model with the following effects: treatment, study center, opioid status, and baseline RMDQ score.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.28
Confidence Interval (2-Sided) 95%
-1.20 to 0.65
Estimation Comments Placebo - Hydrocodone ER
6.Secondary Outcome
Title Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods
Hide Description An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame Day 1 of Titration Period up to Week 12 of Treatment Period (maximum treatment duration was 127 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set (Titration Period) and Full analysis set (Treatment Period)
Arm/Group Title Opioid-Naive (Open-Label Titration Period) Opioid-Experienced (Open-Label Titration Period) Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:

Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening.

Opioid-naïve participants started at a 15-mg dose of hydrocodone ER tablets every 12 hours.

All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain.

Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening.

For opioid-experienced participants, the starting dose of hydrocodone ER tablets was to be approximately equivalent to 50% of the dose of opioid analgesic that they were receiving at screening and administered every 12 hours.

All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain.

Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 368 255 179 191
Measure Type: Count of Participants
Unit of Measure: Participants
Any adverse event
196
  53.3%
117
  45.9%
88
  49.2%
106
  55.5%
Severe adverse event
13
   3.5%
5
   2.0%
3
   1.7%
9
   4.7%
Treatment-related adverse event
166
  45.1%
81
  31.8%
50
  27.9%
67
  35.1%
Deaths
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Serious adverse event
6
   1.6%
4
   1.6%
3
   1.7%
3
   1.6%
Discontinued study drug treatment due to AE
53
  14.4%
22
   8.6%
7
   3.9%
11
   5.8%
7.Secondary Outcome
Title Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results
Hide Description Pure tone audiometry was performed by a qualified audiologist and was not done at the study center. During the test, the patient wore headphones and was seated in a quiet room; trained personnel manipulated the audiometry equipment to test the patient’s hearing. For serial audiograms, the criteria for a clinically significant (CS) hearing change were based on the guidance from the American Speech-Language Hearing Association (ASHA) 1994 (Konrad-Martin et al 2005). These criteria included the following: greater than 20 decibels (dB) pure tone threshold shift at 1 frequency; greater than 10 dB shift at 2 consecutive test frequencies; or threshold response shifting to “no response” at 3 consecutive test frequencies.
Time Frame Days 7-14 of Titration Period (baseline), Day 0 of Treatment Period (last day of Titration Period), Week 12 or end of study visit during the Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set (entire study), Full analysis set (treatment period)
Arm/Group Title Hydrocodone ER (Safety Analysis Set) Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
All enrolled participants who were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours. Includes days on hydrocodone ER during both the titration and treatment periods.
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 623 179 191
Measure Type: Count of Participants
Unit of Measure: Participants
>= 1 CS value during study
29
   4.7%
10
   5.6%
8
   4.2%
>= CS value during open-label titration period
13
   2.1%
5
   2.8%
2
   1.0%
>= 1 CS during double-blind treatment period NA [1] 
8
   4.5%
6
   3.1%
>=CS value at endpoint NA [1] 
8
   4.5%
7
   3.7%
[1]
See values in Hydrocodone ER (Double-blind Treatment Period) column
8.Secondary Outcome
Title Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period
Hide Description The results of the SOWS were collected in the e-diary daily during the first 4 weeks of the double blind treatment period and then during clinic visits at week 12 or early termination. The SOWS was a self-administered questionnaire used to measure a participant's signs and symptoms of withdrawal from opiates. The scale contained 16 symptoms (such as my nose is running; I feel restless), the participant rated the intensity on a scale of 0 (not at all) to 4 (extremely) for a total score of 0-64. The daily total score for the first 4 weeks was the largest score observed during the time period preceding that visit. For example, the week 1 score for each participant was the largest total score on any day between baseline and the night before the week 1 visit; the week 4 score for each participant was the largest score observed between the week 2 visit and the night before the week 4 visit.
Time Frame Weeks 1, 2, 4 and Endpoint of the Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants contributing to each time point are listed in the time point label.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 179 191
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 1 Number Analyzed 174 participants 186 participants
6.9  (7.03) 6.6  (7.36)
Week 2 Number Analyzed 164 participants 180 participants
5.1  (6.10) 5.1  (6.89)
Week 4 Number Analyzed 151 participants 172 participants
5.0  (5.52) 5.5  (6.58)
Endpoint Number Analyzed 176 participants 189 participants
5.7  (6.70) 6.1  (7.63)
9.Secondary Outcome
Title Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period
Hide Description

COWS is a clinician-rated scale used to measure a participant's signs and symptoms of withdrawal from opiates, with ratings based only on apparent relationship to withdrawal. The COWS was performed at weeks 1, 2, 4, and 12 (double blind treatment period) or early termination. The scale contained 11 signs/symptoms whose intensity the clinician rated on a scale of 0 to 4 or 5.

A total score was calculated as the sum of the responses to the 11 signs/symptoms for a total range of 0-48. Withdrawal severity was classified, based on the total score, as follows:

  • 0 to 4=normal
  • 5 to 12=mild
  • 13 to 24=moderate
  • 25 to 36=moderately severe

    • 36=severe
Time Frame Weeks 1, 2, 4 and Endpoint of the Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants contributing to each time point are listed in the time point label.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 179 191
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 1 Number Analyzed 170 participants 181 participants
0.9  (1.66) 0.8  (1.33)
Week 2 Number Analyzed 161 participants 180 participants
0.8  (1.52) 0.7  (1.13)
Week 4 Number Analyzed 149 participants 167 participants
0.8  (1.33) 0.6  (1.03)
Endpoint Number Analyzed 174 participants 185 participants
0.9  (1.49) 0.7  (1.12)
10.Secondary Outcome
Title Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period
Hide Description

Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values.

Significance criteria:

  • Blood urea nitrogen: >=10.71 mmol/L
  • Creatinine: >=177 μmol/L
  • Uric acid: M>=625, F>=506 μmol/L
  • Alanine aminotransferase (ALT): >=3* upper limit of normal (ULN)
  • Gamma-glutamyl transpeptidase (GGT): >=3* upper limit of normal (ULN)
  • Serum white blood cells: <=3.0 * 10^9/L
  • Hemoglobin: M<=115, F<=95 g/dL
  • Hematocrit: M<0.37, F<0.32 L/L
  • Eosinophils: >=10.0 %
  • Absolute neutrophils: <=1.0 * 10^9/L
  • Urinalysis: Glucose: >=2 unit increase from baseline
Time Frame Day 1 up to Week 12 of the Treatment Period
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set including participants with laboratory assessments. Participants with a postbaseline result for that test are counted in each laboratory tests' label.
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 171 178
Measure Type: Count of Participants
Unit of Measure: Participants
Blood urea nitrogen Number Analyzed 171 participants 178 participants
3
   1.8%
1
   0.6%
Creatinine Number Analyzed 171 participants 178 participants
0
   0.0%
1
   0.6%
Uric acid Number Analyzed 171 participants 178 participants
3
   1.8%
4
   2.2%
ALT Number Analyzed 171 participants 178 participants
1
   0.6%
2
   1.1%
GGT Number Analyzed 171 participants 178 participants
6
   3.5%
5
   2.8%
White blood cells Number Analyzed 167 participants 171 participants
1
   0.6%
0
   0.0%
Hemoglobin Number Analyzed 169 participants 173 participants
1
   0.6%
2
   1.2%
Hematocrit Number Analyzed 169 participants 173 participants
6
   3.6%
3
   1.7%
Eosinophils Number Analyzed 167 participants 171 participants
1
   0.6%
2
   1.2%
Absolute neutrophils Number Analyzed 167 participants 171 participants
1
   0.6%
2
   1.2%
Urine glucose Number Analyzed 168 participants 174 participants
2
   1.2%
3
   1.7%
11.Secondary Outcome
Title Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period
Hide Description

Data represents participants with potentially clinically significant (PCS) vital sign values.

Significance criteria

  • Pulse - high: >=120 and increase of >= 15 beats/minute from baseline
  • Pulse - low: <=50 and decrease of >=15 beats/minute
  • Systolic blood pressure - high: >=180 and increase >=20 mmHg
  • Systolic blood pressure - low: <=90 and decrease >=20 mmHg
  • Diastolic blood pressure - high: >=105 and increase of >=15 mmHg
  • Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg
Time Frame Day 1 to Week 12 of the Treatment Period
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Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 179 191
Measure Type: Count of Participants
Unit of Measure: Participants
Pulse - high
2
   1.1%
1
   0.5%
Pulse - low
1
   0.6%
1
   0.5%
Systolic BP - high
1
   0.6%
2
   1.0%
Systolic BP - low
2
   1.1%
3
   1.6%
Diastolic BP - high
0
   0.0%
3
   1.6%
Diastolic BP - low
0
   0.0%
2
   1.0%
12.Secondary Outcome
Title Participants With Potentially Clinically Significant Abnormal Electrocardiogram Findings During the Double-Blind Treatment Period
Hide Description Data represents the number of participants with potentially clinically significant (PCS) electrocardiogram findings on the final study visit.
Time Frame Final study visit (week 12 or end of treatment visit)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description:
Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo.
Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
Overall Number of Participants Analyzed 179 191
Measure Type: Count of Participants
Unit of Measure: Participants
2
   1.1%
2
   1.0%
Time Frame - Day 1 up to Day 43 (maximum duration) of the Titration Period - Day 1 up to Day 93 (maximum duration) of the Treatment Period
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Hydrocodone ER (Open-Label Titration Period) Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Hide Arm/Group Description All participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours to identify a dosage deemed successful for managing their pain. Participants were administered placebo tablets every 12 hours that matched the dosage deemed successful for managing their pain during the titration period. A step wise, double-blind tapering schedule was implemented during the first 2 weeks of the 12 week, double blind, placebo controlled treatment period to reduce the risk of withdrawal effects in patients randomly assigned to placebo. Participants were administered hydrocodone ER tablets at a dosage deemed successful for managing their pain during the titration period. Dosages of 15, 30, 45, 60, or 90 mg every 12 hours were given for 12 weeks during the double-blind period.
All-Cause Mortality
Hydrocodone ER (Open-Label Titration Period) Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Hydrocodone ER (Open-Label Titration Period) Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/623 (1.61%)      3/179 (1.68%)      3/191 (1.57%)    
Cardiac disorders       
Acute coronary syndrome  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Gastrointestinal disorders       
Pancreatitis  1  0/623 (0.00%)  0 0/179 (0.00%)  0 1/191 (0.52%)  1
General disorders       
Chest pain  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Infections and infestations       
Cellulitis  1  1/623 (0.16%)  1 0/179 (0.00%)  0 1/191 (0.52%)  1
Pneumonia  1  2/623 (0.32%)  2 0/179 (0.00%)  0 0/191 (0.00%)  0
Injury, poisoning and procedural complications       
Accidental overdose  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Laceration  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Tracheal injury  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Metabolism and nutrition disorders       
Hypernatraemia  1  0/623 (0.00%)  0 1/179 (0.56%)  1 0/191 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Rhabdomyolysis  1  0/623 (0.00%)  0 1/179 (0.56%)  1 0/191 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Papillary thyroid cancer  1  0/623 (0.00%)  0 1/179 (0.56%)  1 0/191 (0.00%)  0
Pregnancy, puerperium and perinatal conditions       
Abortion spontaneous  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Psychiatric disorders       
Bipolar disorder  1  0/623 (0.00%)  0 1/179 (0.56%)  1 0/191 (0.00%)  0
Depression  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Panic attack  1  0/623 (0.00%)  0 1/179 (0.56%)  1 1/191 (0.52%)  1
Respiratory, thoracic and mediastinal disorders       
Chronic obstructive pulmonary disease  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Dyspnoea  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Respiratory arrest  1  1/623 (0.16%)  1 0/179 (0.00%)  0 0/191 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Hydrocodone ER (Open-Label Titration Period) Placebo (Double-blind Treatment Period) Hydrocodone ER (Double-blind Treatment Period)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   211/623 (33.87%)      41/179 (22.91%)      58/191 (30.37%)    
Gastrointestinal disorders       
Constipation  1  97/623 (15.57%)  102 8/179 (4.47%)  8 27/191 (14.14%)  29
Nausea  1  98/623 (15.73%)  101 14/179 (7.82%)  16 20/191 (10.47%)  23
Vomiting  1  39/623 (6.26%)  39 6/179 (3.35%)  6 8/191 (4.19%)  8
Infections and infestations       
Upper respiratory tract infection  1  3/623 (0.48%)  3 9/179 (5.03%)  9 8/191 (4.19%)  9
Nervous system disorders       
Dizziness  1  33/623 (5.30%)  35 4/179 (2.23%)  4 2/191 (1.05%)  2
Headache  1  42/623 (6.74%)  44 8/179 (4.47%)  8 11/191 (5.76%)  11
Somnolence  1  36/623 (5.78%)  38 2/179 (1.12%)  2 6/191 (3.14%)  7
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor’s review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor’s designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
Results Point of Contact
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc.
Phone: 215-591-3000
Responsible Party: Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )
ClinicalTrials.gov Identifier: NCT01789970     History of Changes
Other Study ID Numbers: C33237/3103
First Submitted: February 8, 2013
First Posted: February 12, 2013
Results First Submitted: February 19, 2017
Results First Posted: April 5, 2017
Last Update Posted: June 5, 2017